ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer.

Abstract

Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) KrasG12D-driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in KrasG12D-driven LAC was independent of bone marrow-derived immune cells. Furthermore, in KRAS mutant human LAC, there was a significant positive correlation between augmented phospho-ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic KRAS-driven LAC and provide the rationale to employ ADAM17-based therapeutic strategies for targeting KRAS mutant cancers.

• Authors: Mohamed I Saad, Sultan Alhayyani, Louise McLeod, Liang Yu, Mohammad Alanazi, Virginie Deswaerte, Ke Tang, Thierry Jarde, Julian A Smith, Zdenka Prodanovic, Michelle D Tate, Jesse J Balic, D Neil Watkins, Jason E Cain, Steven Bozinovski, Elizabeth Algar, Tomohiro Kohmoto, Hiromichi Ebi, Walter Ferlin, Christoph Garbers, Saleela Ruwanpura, Irit Sagi, Stefan Rose-John, Brendan J Jenkins
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 11 Issue 4 (04 2019) ISSN: 1757-4684 [Electronic] England
• PMID: 30833304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Receptors, Interleukin-6
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• ADAM17 Protein
• ADAM17 protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• ADAM17 Protein (antagonists & inhibitors, metabolism)
• Animals
• Cell Line, Tumor
• Genotype
• Humans
• Lung Neoplasms (pathology)
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mutation
• Phosphorylation
• Proto-Oncogene Proteins p21(ras) (genetics)
• Receptors, Interleukin-6 (metabolism)
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)